Pharmaceutical formulations

ABSTRACT

Syrup formulations comprising water and compacted granulates which are mixture of amoxycillin and clavulanic acid, together with an intra-granular disintegrant.

[0001] The present invention relates to pharmaceutical formulations fororal administration in the treatment of bacterial infections, and toprocesses for the manufacture of such formulations.

[0002] It is known to provide formulations for oral administration inthe form of water-dispersible granules or tablets which may be swallowedor dispersed in water prior to swallowing.

[0003] In one known method of tablet manufacture, an intermediategranulate is prepared comprising an intragranular disintegrant and anactive material such as an antibiotic. This granulate is then mixed withan intergranular disintegrant (and optional other additives including alubricant) and compressed into tablets. Such a process, tablets andgranulate are for example described in EP 0281200A, CA 1199871 and JP3240023A.

[0004] It is desirable that such solid formulations should rapidlydisperse on immersion in water, for example by rapid disintegration oftablets.

[0005] Novel formulations have now been discovered which assist inachieving some of the above-mentioned desirable features.

[0006] The invention therefore provides a tablet formulation having astructure comprising compacted granulates; the granulates comprising atleast one compacted medicament optionally together with anintra-granular disintegrant; the granulates being compacted togetherinto a tablet form together with an extra-granular disintegrant andoptionally also together with an extra-granular lubricant, provided thatif a lubricant is present the amount of lubricant is less than 0.5% byweight of the total tablet.

[0007] In the tablets of this invention the granulates may be in acrushed state resulting from the compaction of the tablet, andconsequently may not have discrete boundaries, or may be sub-divided orbroken up into smaller granulates. The invention is intended to includetablets having such a structure containing crushed granulates.Preferably the size of the granulates is in the range 100 μm to 2 mm,suitably around 1 mm±0.25 mm, maximum dimension.

[0008] The medicament is preferably one which is capable of oralabsorption, in particular β-lactam antibiotics optionally in combinationwith a β-lactamase inhibitor. A preferred antibiotic is amoxycillin, forexample present as a hydrate such as the trihydrate. Amoxycillin may beused alone, or may optionally be used in combination with other β-lactamantibiotics and/or β-lactamase inhibitors such as clavulanic acid orsalts (especially the potassium salt) thereof, for example in a weightratio equivalent to amoxycillin: clavulanic acid in the range 12:1 to1:1 such as around 4:1 or 2:1. Preferably the proportion of theantibiotic in the tablet is 60-98% by weight of the total tablet, in thecase of amoxycillin trihydrate calculated as the weight of thetrihydrate. Preferably the particles of antibiotic in the granulates arein the size range 1 μm to 300 μm, especially 10 μm to 200 μm. A typicalsuitable size distribution of the antibiotic particles is: >200μ 5% orless, 200-100μ 5-15%, 100-50μ 7.5-15%, <50μ 70% or more.

[0009] Suitable intra-granular disintegrants are starches, such as maizestarch and rice starch, cross-linked N-vinyl-2-pyrrolidone (“CLPVP”),sodium starch glycollate, croscarmellose sodium and formaldehyde—casein,or combinations thereof. A preferred intra-granular disintegrant isCLPVP, for example as marketed under the trade names Polyplasdone XL andPolyplasdone XL-10.

[0010] The granulate may consist entirely of antibiotic(s), optionallyin the case of a β-lactam antibiotic combined with a β-lactamaseinhibitor, and an intra-granular disintegrant. Alternatively,particularly when the granulate contains clavulanic acid or a saltthereof, the granulate may also contain a diluent such as silica gel (egSyloid-Trade Mark). Suitable intra-granular disintegrants for use withantibiotics are CLPVP and sodium starch glycollate. Typically theproportion of intra-granular disintegrantin the granulate maybe 0.1-10wt % of the granulate, suitably 1.0-8.0 wt %, such as 1.25-3.5 wt %.Typically the proportion of an antibiotic or antibiotic +β-lactamaseinhibitor combination in the granulate may be 99.9-90 wt %, suitably99-92 wt %, e.g. 99-95 wt %, such as 98.75-96.5 wt % of the weight ofthe granulate. When the granulate contains a diluent, this may compriseup to 30 wt % of the granulate, but is conveniently present in a 1:1weight ratio with the amount of clavulanic acid or its salt in thegranulate. When the granulate contains a diluent the granulate willcontain a correspondingly lower proportion of antibiotic or antibiotic+β-lactamase inhibitor combination, for example 70-99.9 wt % of thegranulate.

[0011] The intimate contact between the antibiotic and theintra-granular disintegrant in the granulate appears to assist inimproved disintegration and dispersion of the granulate in contact withwater to release antibiotic particles in the size range referred toabove, and to provide finely dispersed suspensions. Problems areassociated with preparation of granulates which include clavulanic acidor its salts, due to their hygroscopicity, and the granulate of theinvention facilitates manufacture.

[0012] In the tablet formulation the granulate may suitably comprise 70%or more, e.g. 80% or more, 90% or more or 95% or more of the totaltablet weight so that a high proportion of medicament is present.

[0013] The extra-granular disintegrant may be a conventionaldisintegrant for example starches such as maize-starch and rice starch,CLPVP, sodium starch glycollate, croscarmellose sodium, microcrystallineor microfine cellulose, low-substituted hydroxypropylcellulose (i.e.cellulose partially substituted with 2-hydroxypropyl groups, e.g. lessthan 25% substituted, preferably 7-16% substituted), cross-linked sodiumcarboxymethylcellulose, swellable ion exchange resins,formaldehyde-casein, or alginates. Preferred extra-granulardisintegrants are CLPVP, sodium starch glycollate, microfine celluloseand croscarmellose sodium, and combinations thereof. An example of anextra-granular disintegrant combination is a combination ofmicrocrystalline or microfine cellulose with sodium starch glycollate,croscarmellose sodium, or CLPVP, containing 80-90% by weight cellulose.

[0014] The proportion of extra-granular disintegrant to total tabletweight may vary between broad limits, for example 0.1-25 weight %. Forexample if CLPVP or sodium starch glycollate is used as extra-granulardisintegrant it may suitably be used as such in a proportion 0.1-5.0weight %, suitably 0.1-3.0 weight %, preferably 0.1-1.5 weight % of thetotal tablet weight. If cellulose or a combination containing celluloseis used, e.g. as described above containing around 80-90% by weight ofcellulose, the extra-granular disintegrant may comprise 1-25 weight %,typically around 1-20 weight % of the total tablet.

[0015] Suitable lubricants are those conventional to the art, such aslong-chain fatty acids, such as stearic acid, or salts thereof, inparticular Group II metal salts, such as of magnesium or calcium.

[0016] A preferred lubricant is magnesium stearate. It is preferred touse a lubricant proportion as low as possible e.g. 0.35% by weight orpreferably lower, e.g. 0.275% or less, e.g. 0.25% or less, preferablyusing no lubricant at all.

[0017] The granulate may also contain an intra-granular lubricant, whichmay be selected from the same materials as the extra-granular lubricant,such as magnesium stearate. However an advantage of the present tabletformulation is that the granulate and tablet need not contain anylubricant. This can lead to improved wettability and hence improveddisintegration of the tablet. Further a reduced lubricant proportion canlead to a lower tablet weight for a given dose of antibiotic and in thecase of dispersible formulations can avoid the “smeared” appearanceassociated with higher lubricant proportions.

[0018] The tablet may also include conventional excipients, typicallypresent up to about 10% of the total tablet weight. These may includeflavouring agents, for example flavourings such as menthol, peppermint,vanilla or fruit flavourings, flavouring agents typically being presentup to around 0.5-5% by weight of the whole tablet, and sweeteners, e.g.aspartame, present of up to around 15 mg per unit dose. Excipients mayalso include colouring agents, preservatives, suspending aids andfillers such as silicon dioxide, microcrystalline cellulose, dicalciumphosphate, lactose, sorbitol, calcium carbonate or magnesium carbonate.Such excipients are preferably mixed with the extra-granulardisintegrant and lubricant (if present). The materials present in thetablets should have low free moisture content and preferably bepre-dried. In some cases, particularly when the medicament is anantibiotic, and includes clavulanic acid or its salts, it may benecessary to include a dessiccant diluent such as silica gel as anexcipient, in a proportion of about 1-5% of the weight of theantibiotic, mixed with the antibiotic and intra-granular disintegrant inthe granulates. The particle size of the excipients does not appear tobe critical but it is desirable to exclude agglomerates.

[0019] The tablet may also contain an effervescent couple of known type,e.g. a solid acid and an alkali metal carbonate or bicarbonate whichgenerates carbon dioxide on contact with water to assist indisintegration of the tablet.

[0020] The tablets may be film coated in a conventional manner, e.g. forcosmetic, palatability or production purposes. Suitable coatings includehydroxypropylcellulose, acrylate and/or methacrylate co-polymers, resinsetc. Alternatively the coating may be an enteric coating, e.g. which isinsoluble in acidic gastric juice but soluble in alkaline digestivejuice. Such a coating enables the antibiotic to pass through the stomachinto the duodenum, from where it is absorbed. Suitable enteric coatingsinclude cellulose acetate phthalate.

[0021] Preferred combinations of components for the tablets of thisaspect of the invention therefore comprise: Component wt % ExampleGranulate: Medicament  70-99 Amoxycillin ± Pot.clavulanate Disintegrant0.1-4  CLPVP, Microcryst. cellulose, sodium starch glycollate Diluent  0-30 Silica gel Tablet: Granulate 70+ above Disiutegrant 0.1-25 CLPVP,Microcryst. cellulose, sodium starch glycollate. Lubricant  0-0.35Magnesium stearate Excipients to 100 Aspartame, flavour, colour, silicondioxide

[0022] The invention also provides a process for the manufacture of atablet in which granulates comprising a compacted mixture of at leastone medicament such as a β-lactam antibiotic either alone or incombination with a β-lactamase inhibitor, together with anintra-granular disintegrant are mixed with an extra-granulardisintegrant and optionally with an extra-granular lubricant andoptionally with any excipients, provided that if a lubricant is presentit amounts to less than 0.5% by weight of the mixture, and the mixtureis compressed into tablets.

[0023] Suitable and preferred antibiotics, intra- and extra-granulardisintegrants, lubricants, excipients, granulate and particle sizes, andrelative proportions thereof are as discussed above.

[0024] The necessary granulate for the process of this aspect of theinvention may be made in a further process by mixing the medicament in apowdered form with the intra-granular disintegrant in a dry state, andcompacting the mixture under pressure. Insofar as this further processuses as intra-granular disintegrant CLPVP, sodium starch glycollate,casein-formaldehyde, croscarmellose sodium or combinations thereof, itis believed to be novel, and is a further aspect of this invention.

[0025] In this further process, it is desirable to mill and sieve theantibiotic to achieve the desired particle size range. It is alsodesirable to mill and sieve intra-granular disintegrant to a suitableparticle size, for example in the case of CLPVP about 30μ, but particlesize does not appear to be critical.

[0026] The compaction of the mixture into granulates may be byconventional dry compaction means, for example pressing, rolling,slugging extrusion etc, and a suitable pressure for the compactionprocess is 30-200KN, e.g. 35-65KN preferably 40-50 KN. Theabove-described granulate formulations are particularly suited toformation by roller compaction. It may be necessary to mill and sievethe compacted mixture after compaction so as to achieve a suitable sizefraction of the granulate. Compression into tablets may be carried outin a conventional manner, e.g. on a conventional tabletting machine. Asan optional further step the tablets may be coated as described above.

[0027] When the granulates described above contain as a medicament aβ-lactam antibiotic such as amoxycillin together in combination with aβ-lactamase inhibitor such as clavulanic acid or its salts (especiallypotassium clavulanate) these granulates are believed to be novel and area further aspect of this invention. Suitable and preferred features ofthese granules are as discussed above.

[0028] The granulates described above may be suitable for use in thepreparation of other pharmaceutical formulations in addition to tablets,for example they may be supplied as a free-flowing granulatedformulation in sachets containing a suitable unit dose. This may alsofor example be dissolved in water together with excipients such assweetening agents, thickeners, preservatives and buffers such as sodiumbenzoate, sodium acetate and sodium citrate to form a syrup formulation,for example for administration to small children.

[0029] The ability of the granulates to form a loose compact, and theirrapid dispersion in contact with water makes them particularly suitablefor use in encapsulated formulations. Therefore in a further aspect ofthis invention there is provided an encapsulated formulation comprisingsuch granulates. The encapsulated formulation may optionally include anextra-granular lubricant, which if present is suitably in an amount ofless than 0.5% by weight of the granulates, being contained within apharmaceutical capsule.

[0030] The medicament is preferably one which is capable of oralabsorption, in particular a β-lactam antibiotic optionally incombination with a β-lactamase inhibitor. Suitable and preferredantibiotics, β-lactamase inhibitors, intra-granular disintegrant,extra-granular lubricant, granulate and particle sizes, and relativeproportions thereof for a capsule formulation are as discussed above,except that a preferred proportion of lubricant is 0.1-0.5%,particularly 0.32-0.35% by weight of the granulate.

[0031] The pharmaceutical capsule may be an entirely conventionalcapsule, capable of dissolving in the stomach to release its contents,for example made of gelatine.

[0032] The formulations described above preferably contain unit doses ofantibiotic, for example 375, 500, 750 or 1000 mg of amoxycillin pertablet or capsule. The tablets may be dispersed in water prior toingestion, or may alternatively be chewed or swallowed whole.

[0033] The invention further provides a pharmaceutical formulation asdescribed above, for use as an active therapeutic substance.

[0034] The invention further provides a pharmaceutical formulation asdescribed above, in which the medicament is a β-lactam antibioticoptionally in combination with a β-lactamase inhibitor, for use in thetreatment of bacterial infections.

[0035] The invention futher provides a method of use of a pharmaceuticalformulation as described above in which the medicament is a β-lactamantibiotic optionally in combination with a β-lactamase inhibitor in themanufacture of a medicament for use in the treatment of bacterialinfections.

[0036] The invention further provides a method of treament of bacterialinfections in mammals which comprises the administration to the mammalof an effective amount of a pharmaceutical formulation as describedabove, in whcih the medicament is a β-lactam antibiotic, optionally incombination with a β-lactamase inhibitor.

[0037] The invention will now be described by way of example only.

Example 1 Granulate

[0038] Amoxycillin trihydrate was milled and sieved using an 0.04 or0.027 inch (1.0-0.7 mm) aperture sieve, and was mixed for 15 minutes ina blender with dried cross-linked polyvinylpyrrolidone having amolecular weight of approximately 1 million and a density of 1.22 mg/cm3 (polyplasdone XL - Trade Mark), the mixture containing 3.4% of CLPVPby weight.

[0039] The mixture was consolidated using a roller compacter at acontrolled pressure of 50KN. The compacted flakes were granulated in amill, or granulated through a sieve fitted with a 1 mm mesh to obtain asuitable size fraction.

Example 2 Tablet

[0040] Tablets were prepared having the composition below; ComponentWeight mg. Weight % Amoxycillin trihydrate  750¹ 78.95 as granulate ofCLPVP 26.0 2.73 example 1 Sodium Starch 21.6 2.27 Glycollate (Primogel)Magnesium Stearate 2.0 0.21 granulate Aspartame 20.0 2.10Microcrystalline 130.4 13.74 Cellulose (Avicel PH102)

[0041] To prepare these tablets, the dried sodium starch glycollate,magnesium stearate and microcrystalline cellulose were sieved, thenblended with the granulate of example 1. The aspartame was then added,and this mixture was then blended until homogeneous (5 minutes). Themixture was then compressed into tablets on a conventional tablettingmachine.

Example 3 Granulate

[0042] A granulate was prepared using a procedure identical to example1, comprising 97 weight % of amoxycillin trihydrate and 3 weight %polyplasdone XL, and using a controlled pressure of 40-50 KN.

Example 4 Tablet

[0043] Tablets were prepared having the composition below: Component wt.mg wt. mg wt. mg wt. mg wt. % Amoxycillin 375 500 750 1000 83.00¹ CLPVP17.5 23.33 35 46.65 3.78² Peppermint 3 4 6 7.99 0.65 dry flavourAspartame 7.5 10 15 19.99 1.62 Magnesium 1 1.34 2 2.67 0.21 stearate

[0044] To prepare these tablets, the dried flavour, aspartame, magnesiumstearate and a weight of CLPVP (polyplasdone XL) corresponding to 0.78wt. % of the total weight of the mixture was mixed for 5 minutes withthe granulate of example 3 to give the wt % indicated above. The mixturewas then compressed into tablets on a conventional tabletting machine.

[0045] Typical tablets of this example containing 750 mg of amoxycillinas the trihydrate had the following characteristics: weight 925 mg ± 5%hardness >16 KP time of dispersal <1 minute in water friability <1%presentation Oval, 17 × 10 × 7 mm tablets

Example 5 Granulate

[0046] A granulate was prepared using a procedure identical to that ofexample 1, comprising 97.12 weight % amoxycillin trihydrate togetherwith 2.88 weight % sodium starch glycollate (as “Primogel”) asintra-granular disintegrant.

Example 6 Tablet

[0047] Tablets were prepared having the composition below: Component %Weight mg. Weight % Amoxycillin 750 mg¹ 78.95 as granulate Sodium starch21.6 mg 2.27 of example 5 glycollate Magnesium stearate 2.0 mg 0.21extra Dried microcrystalline to 950 mg 18.57 granulate cellulose (AvicelPH102)

[0048] To prepare these tablets, the granulate of example 5 was sievedusing a 1 mm sieve, and was then blended with appropriate quantities ofthe magnesium stearate (lubricant) and microcrystalline cellulose,mixing for 15 minutes. The mixture was then compacted to form tabletshaving the following characteristics: weight 950 mg hardness 12-16 KPtime of dispersal 10-15 seconds (37° C.), in water 20-25 seconds (20°C.)

[0049] These tablets could be provided in the above-described uncoatedstate for dispersion in water prior to swollowing, or could be filmcoated for swollowing.

Example 7 Encapsulated Formulation

[0050] The granulate of example 3 was made up into a loose compact undergentle pressure together with an amount of magnesium stearate lubricantto total 0.34% by weight of the total compact. This loose compact wassealed into gelatin capsules containing the following mixture: ComponentWeight mg. Weight % Amoxycillin trihydxate  573.91¹ 96.8 CLPVP 17 2.9magnesium stearate 2 0.34

Example 8 Sachet Formulation

[0051] Component Weight mg. Weight % Amoxydillin trihydrate Potassium2711.1 76.12 granulate clavulanate/syloid AL-1 blend 1:1 Polyplasdone XLdried Polyplasdone XL dried 13.5 0.38 Lemon dry flavour 408.0 11.4 extragranular Strawberry dry flavour 132.0 3.71 Peach dry flavour 102.0 2.86Aspartame 45.0 1.26 Xautham Gum 150.0 4.21

[0052] Granules were in a manner identical to that of example 1, i.e. bymilling and sieving of the granulate components, followed by rollercompaction (50KN) and granulation. The granules could be made up into amixture suitable for a sachet presentation with the extra-granularexcipients.

[0053] The granulate of this example could be supplied confiningappropriate weights of amoxycillin/clavulanate in a sachet, and is alsosuitable for making up into syrup formulations. For example the weightslisted may be made up into 60 ml to produce a 156.25 mg/5 ml syrup ordouble the listed weights may be made up into 60 ml to produce a 312.5mg.5 ml syrup. These syrups do not contain any added sugar.

Example 9 Granulate

[0054] Component Weight mg. Weight % Amoxycillin trihydrate 581.4¹ 64.0Potassium clavulanate 152.4² 16.8 as granulate Syloid AL-1 152.4 16.8Polyplasdone XL dried 22.0 2.42

[0055] Granules are prepared using this mixture in a manner identical tothat of example 8. These granules are suitable for supply in a sachet,together with flavour and sucrose in the proportions listed below forthe quantity of granules listed above per sachet: Lemon dry flavour136.6 mg Strawberry dry flavour 44.0 mg Peach dry flavour 34.0 mgSucrose to 3500 mg

[0056] Sachets containing other weights of amoxycillin, e.g. 250 or 125mg could be made up using proportional amounts of the weights listed andmade up to 1750 mg total weight with sucrose.

Example 10 Tablet

[0057] Component Weight mg. Weight % Amoxycillin trihydrate 581.4¹ 61.2Potassium clavulanate 152.4² 16.0 as granulate Syloid AL-1 152.4 16.0Polyplasdone XL dried 17.4 1.83 Dry flavour (Peppermint or 6.0 0.63mandarin) Polyplasdone XL dried 25.0 2.63 extra granulate Aspartame 15.01.58 Colouring 5.0 0.53 Magnesium stearate 2.5 0.26

[0058] Granules are prepared using this mixture in a manner identical tothat of example 8. The flavour, polyplasdone XL, colouring and magnesiumstearate were sieved then blended with the granulate. The aspartame wasthen added, and this mixture was then compressed into tablets on aconventional tabletting machine. This tablet contains 625.0 mg of theamoxycillin: clavulanate combination, and the quantities used may behalved to prepare a tablet containing 312.5 mg.

Example 11 Tablet

[0059] Component Weight mg. Weight % Amoxycillin trihydrate 290.7¹ 46.3Potassium clavulanate 152.4² 24.3 Syloid AL-1 152.4 24.3 {close oversizebracket} as granulate Polyplasdone XL dried 8.7 1.38 Dry flavour(Peppermint 3.0 0.48 or mandarin) Polyplasdone XL dried 12.5 2.00Aspartame 7.5 1.19 {close oversize bracket} extra granulate Colouring2.5 0.39 Magnesium stearate 1.25 0.20

[0060] Tablets were made from this mixture using a procedure identicalto that of example 10.

Example 12 Sachet or Syrup Formulations

[0061] Component Weight mg w + % Amoxycillin: potassium 2255.6 63.3clavulanate {close oversize bracket} granulate¹ 4:1 w:w + 3 wt % CLPVPCLPVP 13.5 0.38 Lemon dry flavour 408.0 11.46 Strawberry dry flavour132.0 3.71 Peach dry flavour 102.0 2.86 Silicon dioxide USNF 450.0 12.64(Syloid AL-1) Aspartame 45.0 1.26 Xantham gum 150.0 4.21 Total weight3561.6 100.0

[0062] (1) amox:clav expressed as free acid.

[0063] The granulate was prepared using the procedure of example 8. Thisformulation could be supplied in a sachet, or could be made up into asyrup, for example at concentrations of 3561.6 mg/60 ml or 7123.2 mg/60ml or 7123.2 mg/60 ml (=156.25 and 312.5 mg amoxycillin:clavulanate/5 mlrespectively). To adjust the syrup to a suitable viscosity and pH,aerosil 200, succinic acid and/or methocel E-15 (dry) may be used.

Example 13 Sachet Formulation

[0064] Weight (mg) w + % Granulate (Amox:Kclav {close oversize bracket}500 250 125 875   7-25 4:1 or 7:1 + 3% PVP) Lemon dry flavour 136 68 34136) Strawberry dry flavour 44 22 11  44)   3-6.1 Peach dry flavour 3417 8.5  34) Silicon Dioxide U.S.N.F. 150 75 37.5 150  2.1-4.3 (SyloidAL-1) Sucrose to 3500 1750 1750 3500  to 100

[0065] The granulate was prepared using the procedure of example 8, andwas then mixed with the other excipients.

Example 14 Tablet Formulation

[0066] Amox:clav¹ 4:1 4:1 2:1 7:1 Component weight (mg) w + % Granulate²751.9 376.0 452.1 1201.3 70.90 Dry Flavour³ 6.0 3.0 3.0 8.0 0.48-0.63Poliplasdone XL) 100.0 50.0 66.5 110.0  8.1-10.7 dried) Aspartame 15.07.5 7.5 15.0 1.1-1.6 Colouring 4-5 2-2.5 2-2.5 4-5  0.3-0.55 Mag.Stearate 2.5 1.25 1.25 3.4 0.19-0.26 Silicon Dioxide) Syloid AL-1) to950 475 628 1350 to 100

[0067] The granulate was prepared using the procedure of example 9.

[0068] The granulate was prepared using the procedure of example 9. Theother excipients except aspartame were sieved and blended then mixedwith the granulate. The aspartame was then added, and this mixture wasthen compressed into tablets in a conventional tabletting machine. Thistablet contained 625 mg of the amoxycillin:clavulante blend. Tablets ofdifferent strengths could be formulated correspondingly, eg containing1000, 375 or 312.5 mg of the amoxycillin:clavulanate combination.

Example 15 Tablet Formulation

[0069] Component Weight (mg) w + % Granulate (Amox.Kclav) {closeoversize bracket} 751.9 376.0 183.0 1201.3 71-83 4:1 or 7:1 + 3% PVPMagnesium stearate {close oversize bracket} 2.6 1.3 0.65 3.9 0.25-0.27Ph. Eur Silicon Dioxide USP/NF {close oversize bracket} 44.0 22.0 11.044.0   3-4.25 (Syloid AL-1) Microcrystalline cellulose Avicel pH 112dried {close oversize bracket} 850.0 425.0 212.5 1275.0 1.8-5   . . . to. . . Organic film coating yes yes yes yes to 100 Actual weight 1050.0 —— 1450.0

[0070] The tablet was made up in a manner identical to that of example14.

[0071] The weights and relative proportions of the components ofexamples 1 to 15 could be varied about the figures listed, but suitablyare within ±10% of those listed, desirably within ±5%, especially ±2.5%.

1. A tablet formulation having a structure comprising compactedgranulates; the granulates comprising at least one compacted medicamentoptionally together with an intra-granular disintegrant; the granulatesbeing compacted together into a tablet form together with anextra-granular disintegrant and optionally also together with anextra-granular lubricant, provided that if a lubricant is present theamount of lubricant is less than 0.5% by weight of the total tablet. 2.A tablet formulation according to claim 1 wherein the medicament is aβ-lactam antibiotic, optionally in combination with a β-lactamaseinhibitor.
 3. A tablet formulation according to claim 2 wherein theantibiotic is amoxycillin, optionally in combination with clavulanicacid or a salt thereof in a weight ratio equivalent toamoxycillin:clavulanic acid in the range 12:1 to 1:1.
 4. A tabletformulation according to claim 1, 2 or 3 wherein the intra-granulardisintegrant is selected from maize starch, rice starch, cross linkedN-vinyl-2-pyrrolidone (“CLPVP”), sodium starch glycollate,croscarmellose sodium, formaldehyde-casein or combinations thereof.
 5. Atablet formulation according to any one of the preceding claims whereinthe proportion of intra-granular disintegrant is 0.1 to 10 wt % of theweight of the granulate.
 6. A tablet formulation according to any one ofclaims 1 to 6 in which the granulate comprises a medicament which isamoxycillin or amoxycillin+clavulanic acid or a salt thereof incombination, an intra-granular disintegrant which is CLPVP or sodiumstarch glycollate, and optionally one or more diluent(s), in aproportion 70-99 wt % medicament, 1-5 wt % disintegrant and up to 30 wt% diluent.
 7. A tablet formulation according to any one of the precedingclaims wherein the granulate comprises 70 wt % or more of the tabletweight.
 8. A tablet formulation according to any one of the precedingclaims in which the extra-granular disintegrant is selected from maizestarch, rice starch, CLPVP, sodium starch glycollate, croscarmellosesodium, microcrystalline or microfine cellulose, low-substitutedhydroxypropylcellulose, cross-linked sodium carboxymethylcellulose,swellable ion exchange resins, formaldehyde-casein, or alginates.
 9. Atablet formulation according to any one of the preceding claims whereinthe proportion of extra-granular disintegrant in the tablet is between0.1-25 wt % of the total tablet weight.
 10. A tablet formulationaccording to any one of the preceding claims which contains 0-0.35 wt %lubricant.
 11. A pharmaceutical granulate formulation comprising amedicament which is a β-lactam antibiotic together in combination with aβ-lactamase inhibitor.
 12. A formulation according to claim 11 whereinthe medicament is amoxycillin in combination with clavulanic acid or asalt thereof in a weight ratio equivalent to amoxycillin:clavulanic acidin the range 12:1 to 1:1.
 13. A formulation according to claim 11 or 12wherein the formulation additionally includes an intra-granulardisintegrant.
 14. A formulation according to claim 13 wherein thedisintegrant is selected from maize starch, CLPVP, sodium starchglycollate, croscarmellose sodium, formaldehyde-casein or combinationsthereof.
 15. A formulation according to claim 13 or 14 wherein theproportion of intra-granular disintegrant is 0.1 to 10 wt % of theformulation.
 16. A formulation according to claim 11 in which thegranulate comprises a medicament which is amoxycillin plus clavulanicacid or a salt thereof in combination, an intra-granular disintegrantwhich is CLPVP or sodium starch glycollate, and optionally one or morediluent(s) in a proportion 70-99 wt % medicament, 1-5 wt % disintegrantand up to 30 wt % diluent.
 17. A formulation according to any one ofclaims 11 to 16 or a granulate as defined in claim 1 or a granulate asdefined in claim 1 when encapsulated in a pharmaceutical capsule.
 18. Aprocess for the manufacture of a pharmaceutical tablet, in whichgranulates comprising at least one compacted medicament optionallytogether with an intra-granular disintegrant are mixed with anextra-granular disintegrant and optionally with an extra granularlubricant and excipients, provided that if a lubricant is present itamounts to less than 0.5 wt % of the mixture, and the mixture iscompressed into tablets.
 19. A process for the manufacture of apharmaceutical granulate, in which a medicament which is a β-lactamantibiotic together in combination with a β-lactamase inhibitor iscompacted under pressure, optionally together with an intra-granulardisintegrant.
 20. A process according to claim 19 wherein the compactionis carried out using roller compaction.
 21. A pharmaceutical formulationaccording to any one of claims 1 to 17 for use as an active therapeuticsubstance.
 22. A pharmaceutical formulation according to any one ofclaims 1 to 17, in which the medicament is a β-lactam antibioticoptionally in combination with a β-lactamase inhibitor, for use in thetreatment of bacterial infections.
 23. A method of use of apharmaceutical formulation according to any one of claims 1 to 17 inwhich the medicament is a β-lactam antibiotic optionally in combinationwith a β-lactamase inhibitor, in the manufacture of a medicament for usein the treatment of bacterial infections.